Chemoresistance and targeted therapies in ovarian and endometrial cancers

Abstract

Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers.

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

“…EGFR activates the RAS/RAF/MAPK pathway and the PI3K/Akt pathway, which leads to activation of c-Myc and cyclin D1. Members of the ERBB family of receptors serve key roles in chemoresistance (5,22). FGF stimulates SRC proto-oncogene/focal adhesion kinase, SRC/PI3K/Akt, Hedgehog, Notch, transforming growth factor-β and noncanonical WNT signaling cascades and regulates a variety of cellular functions (5,21,22).…”

“…Mucinous tumors are more frequently detected in early-stage disease with lower tumor grading compared with high-grade serous cancer; however, patients with advanced disease have poor clinical outcome, possibly due to resistance to taxane and platinum-based conventional chemotherapy (4). An evolutionarily conserved signaling cascade system, including growth factor pathways [epidermal growth factor receptor (EGFR), ERBB and fibroblast growth factor receptor (FGFR)] and Wingless (WNT) signaling pathways, regulates a variety of cellular functions, including chemoresistance (5). The crosstalk between EGFR/KRAS proto-oncogene/B-Raf proto-oncogene (BRAF)/mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K)/Akt (also known as protein kinase B) and WNT signaling pathways sustains PI3K/glycogen synthase kinase-3β (GSK3β)/β-catenin signal activation, which is associated with chemoresistance in cancer (6).…”

“…The crosstalk between EGFR/KRAS proto-oncogene/B-Raf proto-oncogene (BRAF)/mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K)/Akt (also known as protein kinase B) and WNT signaling pathways sustains PI3K/glycogen synthase kinase-3β (GSK3β)/β-catenin signal activation, which is associated with chemoresistance in cancer (6). The WNT receptors and their downstream components are being investigated as potential targets in the development of novel anticancer therapies (5,6).…”

Combination of Cisplatin-Withaferin Based on PEGylated Liposome Nanoparticles as Alternative Therapy for Ovarian Cancer

“…yang berarti tidak ada yang menginduksi apoptosis. 13,14 Penggunaan cisplatin secara tunggal sebagai agen kemoterapi juga sering menimbulkan efek samping seperti mual muntah, hepatotoksisitas, dan neurotoksisitas. Untuk mengurangi efek samping dan resistensi dari cisplatin tersebut, diperlukan kombinasi terapi cisplatin dengan senyawa herbal.…”

Restoration of microRNA‐708 sensitizes ovarian cancer cells to cisplatin via IGF2BP1/Akt pathway

“…Development of drug resistance limits the efficacy of chemotherapy (Brozovic, ). Several signaling pathways in particular Akt are involved in the cellular response to cytotoxic agents (Zhou et al, ; Brasseur et al, ). It has been reported that activation of Akt signaling contributes to cisplatin resistance in ovarian cancer cells induced by chemokine (C‐C motif) ligand 5 (Zhou et al, ).…”